For the morning. Maybe let's start there. Welcome to Chardan's ninth annual Genetic Medicines Conference. Before we begin, let me share the compliance statement. It covers the presentations today. Our conference presenters have attested and agreed that they will not share or discuss any material, non-public or confidential information that they are aware of. Great. All right. With that out of the way, welcome everyone to this session focusing on the next wave of technologies and programs in the genome editing space. I'm Gula Lifshitz, a Biotech Analyst at Chardan. Investors that have been following the genome editing space have probably seen that genome editing works. We have great efficacy for ex vivo and in vivo LNP delivered liver editing programs among the first wave of programs that we've seen so far. We saw the clinical data aligning nicely with data from preclinical models.
As those mature, we're seeing additional waves of programs that are coming through. Some of those are using similar technologies. Some are using precision editing approaches and some with innovation around delivery. There's also been some ongoing debate regarding the commercial case for some of these one-time genome editing therapies across indication types and market sizes. In this session, we'll discuss how companies are approaching the scientific, clinical, and commercial challenges that are facing the next wave of editing programs. I'm joined by our guests. We have Devyn Smith, CEO of Arbor, Gilmore O'Neill, CEO of Editas , Allan Reine, CEO of Prime , Emma Wang, Co-founder and CTO of YolTech , and Tian Zhu, Co-founder and CEO of GenEdit Bio. Thank you all for joining us today. To start with, I'll ask each of our participants to briefly introduce themselves and their companies, technologies, and programs.
Maybe let's start on this end.
Good morning, everyone. Thanks for the invitation. It's a great pleasure to be here. My name is Emma Wang. Our CEO couldn't make it, so you get me instead. YolTech Therapeutics is a small biotech company based in Shanghai, founded a little more than four years ago. We focus on the development of in vivo genome editing therapies. We are a little more than four years in business. We have five programs in the clinic. Hopefully, our first program will interface to redevelopment at the beginning of next year, which is a China program. Our pipeline programs cover indications from ultra-rare disease with a global patient population of around 10,000 people, all the way to chronic cardiovascular disease. We cover the whole spectrum. We continue to work on other novel indications and diseases to further explore the potential for gene editing.
Great. Gil.
Great. Yeah, good morning, everyone. My name is Gilmore O'Neill, CEO of Editas Medicine. We are an in vivo CRISPR gene editing company focused entirely on in vivo leveraging LNPs, both targeting LNPs for extra hepatic delivery as well as liver delivery. We are focused on the development of low cost of goods, high efficacy, differentiated medicines. Our lead program, EDIT-401, upregulates LDL receptor, has had significant impact, 90% reduction in LDL-C, and is going into the clinic next year with what we hope is a human POC by the end of 2026. The beauty of that indication we see is that it actually can potentially, in the future, address a prevalent population, but has niche populations within it that will actually sort of help drive that sweet spot for speed and regulatory comfort in its approval.
Go ahead.
Hi, everyone. It's Tian Zhu. I'm CEO and a co-founder of GenEdit Bio. We are an in vivo genome editing company based in Hong Kong, Beijing, and Boston. Our aim is to provide affordable DNA surgeries to genetic diseases and beyond. We have a platform and also a pipeline. Our platform includes the proprietary protein delivery vehicle. It's similar to an engineered virus-like particle to encapsulate the RNP form of the CRISPR and sgRNA. We also have a versatile editor that could do site-specific insertion of large fragments. In pipeline, our first pipeline is eye diseases. It's called TGFBI mutant corneal dystrophy, which is autosomal dominant like gain of function mutation diseases. We have dosed four patients from IIT setting in China and aim to file IND to FDA at the end of this year and open global phase one/two development early next year.
The second pipeline is we try to do site-specific insertion of the CAR for in vivo cell therapy. Very nice meeting everyone.
Hi, I'm Allan Reine, CEO of Prime Medicine. We're a company that was founded around prime editing and owned the IP estate around prime editing, which came out of David Liu's lab in 2019, invented in 2019. Think of this as a gene editing technology that can really do any type of edit. Without going into too much detail, we can actually, using an enzyme, transcribe genetic code or base pairs directly into your DNA to make a permanent change. Through that technology, we can do a whole host of different sort of mutations that can't be addressed through other gene editing approaches. We do that using what we call sort of a modified Cas enzyme. It's a nickase where you're making a single stranded break.
As you think about sort of side effect or off target or other things that can happen, it's a very gentle way to edit the genome. Our programs that we're focused on today are predominantly for liver disease or liver-directed programs. Wilson's disease, which is going to IND in the first half of next year, alpha-1 antitrypsin deficiency with an IND mid next year. We're also working on cystic fibrosis with the Cystic Fibrosis Foundation and ex vivo CAR T cell therapies in oncology, immunology, hematology with Bristol Myers.
Morning. Devyn Smith, CEO at Arbor . We, like everyone else here, do genome editing. We are purely focused in vivo ourselves, although we do have partnerships on the ex vivo side, as similar to Prime Medicine. We have a two-pronged approach, as it goes for gene editing. First, we do have a pretty broad platform of editing approaches that were all discovered de novo. Our co-founders, Feng Zhang and David Walt, built the company on idea, not on IP. We have been able to go out and find novel approaches for editing that allow us to have very small technologies so we can become delivery agnostic. We have a couple of liver programs.
Importantly, moving out of the liver, we have a couple of programs targeting in the CNS because we feel there are a lot of really cool targets in the liver, but there's also a lot of really cool companies going after the same targets in the liver. For us, being able to move outside of the liver is an important sort of step for, I think, all of us and doing so as quickly as possible.
Great. With that, let's dive into some of the topics that I mentioned earlier. We'll start with technology. Genome editing has expanded over the last several years. The field now encompasses several different technologies. There's nuclease editing, base editing, prime editing, epigenome editing, and other approaches as well. Initially, there was a lot of discussion about this as first gen, that's second gen, that's third gen. Now, as these technologies start to mature and we're starting to see some divergence in strategy there, what is the latest thinking about how these technologies will coexist and evolve together in this space? Does one supplant the other? Are there opportunities more broadly? I'd like to keep this conversational, so maybe you can jump in on this, Gil.
Can I just go and just say that I actually think that all these technologies, I think, will coexist in the ecosystem. I think the most important thing I've learned over 20+ years of drug development, in the end, it's the product. This is a guy who led the development of DMF as an oral therapy for MS, which was transformative and probably the single biggest medicine that Biogen has ever actually launched. We launched DMF, dimethyl fumarate. Just think about the chemistry there in 2013. I think it's a really good example of how it's about the product and the profile. I think that the different tools and the way we use CRISPR have strengths and, dare I say, weaknesses. What you have to do is you can direct them to places that they can actually have the greatest effect.
I think Allan pointed out how Prime can actually make edits. I think the base editing that is also used by Devyn and my colleagues also have approvals. You have insertional. Obviously, we can actually do direct editing of the regulatory elements to functionally upregulate rescue proteins, which could be agnostic to mutations. The way we use these technologies and the products we create, I think, allows us to coexist. I think that's the key area for focus in therapeutics development.
Yeah, that makes sense. Anyone else with anything?
Yeah, I mean, I think that was really well said. I just would add a couple of things. I really agree. I think these technologies will coexist. We kind of look at it as sort of what's the problem you're trying to solve and what's the best tool to take to that problem, but also sort of how differentiated are you to do something with prime editing that's being done with CRISPR or base editing today. When we're evaluating a program, we want to look at it and say, do we think we can be, obviously, you want to be first. If you're not first, are we going to be best? Oftentimes, as we look at the profiles for certain approaches that we've seen, and it could be CRISPR, could be base editing, where we've seen, look, like this is a pretty good approach.
Maybe we could have a better off target or something else going on here. On balance, we think they've solved the problem pretty well. It really wouldn't make sense for us to develop there. I think we all kind of look at it in the same way. I'm going to agree with Devyn as well. I think there's way too many companies going after the same target in many different areas. That's a debate we can have as well. Yeah, I think there's a lot of reason for these technologies to coexist.
I think.
Go ahead, .
I think Allan hit on the head, which is, and you mentioned this too, I think the strategies are diverging, whereas a few years ago, it was kind of unclear, right? We were all kind of trying to figure out where things sit. I think that ultimately, as Gilmore said, it comes down to the product and how do we differentiate what we're doing. I think as this matures into a true modality, we have to take much more of a modality approach. Find the right target and then find the right tool or approach that actually can alter that target no matter what it may be. I think you're starting to see that maturation, which is a normal maturation of a new modality, which is exciting because it's here to stay. It's going to revolutionize patients' lives.
Not in every disease, but there will be diseases where CRISPR-based approaches will revolutionize patients' treatments.
What are some of the lessons learned from the first wave of therapies that we've seen, some of which have moved on to phase three trials or the commercial space, and some of which have been deprioritized by some of you folks here? What are the lessons learned that you can apply going forward? Anyone?
I'm just going to go for it. Forgive me. I think you actually summarized it very nicely. I think there are a couple of things we've learned on the technical side, which is that these editing tools are incredibly powerful. The technical probability of success in translation preclinical to clinic is unprecedented, I would argue, if you actually look at the rates over the last few years. The second is you can move actually very quickly. We thought we were moving quickly. I'm sitting with my colleagues who are moving even faster. That actually shows what's possible with this technology. I think that Tim Hunt earlier in our session talked about the platform capability. In fact, I think the potential for platform for genome editing is very real. I think that's demonstrated by what we've learned over the last few years.
The other thing that we have learned is the need to focus, which we're all doing, to try and differentiate, really critically differentiate from other products, which I think we are doing. Finally, to really think about the business case. I think the good thing is sometimes you just have to spend time working with people to point out that not only can we give a superior product, but that a one-and-done therapy is viable. I think it was, again, very reassuring in the earlier session to hear from Tim Hunt comments from senior leadership of CMS, which is we actually get the economic argument for a one-and-done therapeutic. I think overall that has actually, I think that has been an important lesson.
I would share that we always learn from the first peers. I think delivery is everything. It's very, very important. Previously, we see that it's equally important as the editor. Comparing to the editor, I think delivery is really the key. We have to invest on delivery. The delivery and the editor actually have to be optimized together. I think indication choice is very important. As Gil said, the technology success may not necessarily translate to the commercial viability. Clinical significance is also very important. Thank you.
Yeah. I mean, maybe staying on the delivery topic, and maybe we can come back to other points after. I mean, Tian, you guys are developing this PDV technologies. Can you expand on how that differentiates and what's different about that versus LNPs?
Sure. I think the first thing we want to develop with the PDVs, actually, we try to encapsulate the cargo diversity to DNA and also the RNP form. RNP form, in our view, in our company's view, is very important to minimize the off-target potential because it's really transient. It's already protein with the sgRNA. That's the focus aim. The PDV could encapsulate DNA, RNP, mRNA, or RNA form and make it very diverse. We can do a lot of engineering work outside, like do glycoprotein pseudotyping and also do antibody conjugation to make it a tissue-specific and cell-specific delivery more precisely. On the CMC point, it's more leveraging the like Lenti similar process. We are also accumulating our own CMC in-house know-hows. Because it's RNP form, the sgRNA does not have to be chemically modified. It's just the sgRNA.
The pain of optimizing the novel Cas, sometimes I'm not sure if Devyn can comment, like it's the sgRNA scaffold and chemical modification. In that form, we have also our own Cas delivery platform. We think this kind of compatibility of the RNP form could accelerate a novel Cas application. Yeah.
Interesting. I guess beyond that, LNPs have really emerged as the, so far, the forerunner for in vivo delivery, at least to the liver. In your experience, are these all the same, or can they really drive a differentiated profile depending on how you design them or what you conjugate to them? I'll leave that open.
Yeah, I mean, I think that they are definitely not all the same. Even you're looking at a number of different components, maybe five, six components that go into an LNP. You could have a targeting moiety, obviously, that can change tissue specificity. Probably the most important component is likely what drives most of the toxicity is the ionizable lipid. There's probably a few different ionizable lipids that have now, in different LNPs, gone into the clinic. I think they're going to have different safety profiles. At the end of the day, it really is all about how you're adjusting that mixture and ratios and everything else that's going to dictate the therapeutic index of your LNP and also which ionizable lipid you are using. We see extremely different profiles based on the LNP that we're using.
We benchmark to the best of our ability on what we believe is being used clinically to see what our therapeutic index looks like. At least so far, against benchmarks, it's looked favorable. I think it's a lot of differences, is what I would say. Everything is not created equal.
I think the other thing that's becoming clear is that I agree with everything that Allan has said. I think the other issue is we're finding that you do have to do some tweaks. The differentiation is not necessarily in the individual components. There are elements there, but it's actually in the totality because the LNP sometimes and the sort of the chemistry, et cetera, has to be modified in the context of the target that you're working with. I still think there's substantial room there for it to be used for a platform.
I was just going to say that.
Notwithstanding that, once you've actually developed it for a given target tissue and target, the simplicity, the simple pieces that you can modify 20 nucleotides on a guide RNA and essentially should be able to reference, in theory, not just from a regulatory point of view, the safety experience, the CMC, etc., but actually also, very importantly, it will substantially diminish the amount of, and this is the beauty of the LNP, the amount of investment that you will have to do for process development, analytics development for your second, third, and fourth indication. The platform isn't just about regulatory designation. It's very much about the level or degree of investment you have to make for the next indications. That matters in selection of indications because the cost-to-value ratio changes. That first indication of the cost-to-value is going to be different.
That numerator and the denominator is going to be different as you go into your second and third indications. I think that is actually something that I think potentially can enable acceleration. It also means that we can actually increase our ambition, the level of ambition and the value creation we can do, not just for moving from rare to more prevalent diseases, but frankly, moving from rare to ultra and supporting ultra-rare diseases.
I think as you move from, it's interesting because if you use the same LNP and you use Cas9 or you do a prime edit or you do a Cas12 or base edit, whatever it is, it's not one size fits all, even with the same LNP because the mRNAs are vastly different in length. The guides are vastly different in length. You have to find the right stoichiometry between the guide and your editing machine, whatever you're putting in within each LNP. There is quite a bit of, I guess, art to the science, as Gilmore said. Once you've got that, if all you're changing is really just the guide element, then it is very plug and play like at that point.
There's some optimization, but really not nearly as much as it would be for starting a different product de novo that was an entirely different technology.
I think just one point to add, because I think it's an important one, is we've now seen multiple examples clinically where we can very safely get to the liver, right? We've seen that now with multiple times of CRISPR, now base editing, and hopefully soon prime editing. We're in a very different place today than we were three or four years ago in terms of we now know we can deliver to that tissue. Hopefully, other tissues will open up. That's a pretty important, I think, inflection point that we've come to in the sector for gene editing.
Emma, what about you guys? You have multiple programs in the clinic now. How are you leveraging that platform capability to move quickly?
Yes. When I started working in this field, it was all about vaccines, right? The vaccine mRNA, the payload, echo what Devyn just said, the payload tends to be shorter. It's the IM LNP. Now in gene editing, we are mostly dosing IV and with larger payload, more two different RNAs instead of one. The formulation has, there's a lot of optimization work on the formulation. On top of that, different ionizable lipids, they have different tropism. Some perform better in the liver. Some perform better in muscle, in T, in HSC. We see all that. We can confirm. I think from our experience, we've been very lucky that we have one of the few clinically validated formulations already used in several of our programs. That helped a lot for us when it comes to communication with FDA.
For example, it has helped to save a lot of non-clinical studies in NHP in mice in long-term durability study. As well, when we communicate with the KOLs and PIs on the clinical development side, the PIs tend to be more willing to take a risk knowing that this part of the product has been validated in the clinic. Definitely, there's a platform advantage. On the CMC side, we know our formulation very well. We know there's good predictability in manufacturing as well. We know what it takes. We have the people, the facility, the instruments, and the process, definitely. Stability. Stability study, people don't often talk about it. It takes a long time to generate data. We could also leverage some of the data as well.
It sounds like there's a lot of synergies across the multiple programs. That makes sense. Devyn, you guys, as you mentioned, are doing some CNS programs where AAV is the more mature delivery technology. Can you talk about how you've approached that part of the delivery equation for those types of programs?
Yeah, I mean, I think if we think about the liver, I think it's pretty well validated, I think, on delivery and on the ability that editing works. We know it works in the liver, and it's durable. There's a clear regulatory path, even in the U.S., and that's been established, I think, over the last couple of years. As we thought about where do we want to go and how do we continue to differentiate, our technology is very small. It can fit into AAV, whether we're doing complex editing with different effectors or excisions, insertions, whatever it may be. It allowed us to really think creatively about where else we could go. The CNS is really, it's the next big horizon, I think, in our industry. We can access the CNS with AAVs today.
From our perspective, it's finding the right indication where you can balance the learnings, but also sort of the risk-benefit of an AAV delivering an editor. We centered in on ALS, where you can access the spinal motor neurons, where the risk-reward there is reasonable. It looks unfortunately a lot like a pancreatic cancer or some other really deadly cancer with no treatment. It is an opportunity, we feel, to potentially deliver value to patients, but also de-risk how do we move outside the liver into a new organ with gene editing. I'm sure it will have all sorts of unforeseen, interesting challenges and opportunities as we do so. It is the time's right, and it's the opportunity, I think, to really move beyond the liver. We are doing that.
Great. Maybe let's shift gears and talk about the commercial and business case for gene editing therapies. As we've already talked about several times here, we've seen some impressive human efficacy data for the clinical stage programs. Oftentimes, when I talk to investors, some of the debate centers are not on the science, but on the commercial prospects, either because a program is advancing in a very rare disease or a subset of patients, or it's a less rare disease where there are some available therapies. The question is the extent of unmet need or demand, for example, in the cardiovascular space. How do you make the commercial case for one-time gene editing within your pipeline indications? Some examples or data to support that would be great.
I'll start on that.
Yeah.
We did a partnership with, announced a partnership with KAZ Pharmaceuticals a couple of weeks ago for our lead program, which is for an ultra-rare pediatric liver indication. In all of our indications, we decide we have to be first in class, particularly when you're in the rare space because, as every patient you dose, your pool shrinks and goes down to zero, which is great for patients. It's a little more difficult when you think about the commercial aspects of it. I think as we have the conversations with KAZ, they have a very large rare disease group. They understand the commercial model. They understand the rare disease space. It's nice to have a partner that is dedicated, understands it, and understands the commercial opportunity. I think, I'll be honest, I've had investors say, why would you want a one-and-done therapy? How do you monetize that completely?
The response is, why don't you call the Wall Street Journal and tell them that? I'm sure the entire, is there anyone here who doesn't want their child or their family member to be treated one-and-done? The commercial model, it will work because we've seen that before. If you have a therapy that's transformational and it works, it will be commercially successful. I think we will demonstrate that. I think Intellia is probably going to be first up on the in vivo side. I have full confidence they'll be successful because these therapies transform patients' lives.
I think just to add or build on what Devyn has said, I think one of the things that I think we need to share and have people fully understand is that we are differentiated. Our approach has been to think about saying, ok, what's the space that we can work in or we have the right to work in with CRISPR? We decided to say we will functionally upregulate. I'll come back to knockdown because there are advantages there too. We have decided to focus on functional upregulation. We're not happy. I think Devyn actually alluded to this as well. It's not sufficient to be mechanistically differentiated. That's great. That's just cool. What you have to do is create a product. We also said that we must have products and develop products that are going to differentiate on efficacy.
With our LDNR program, we believe that a 90% reduction in LDL-C is meaningfully differentiated from other targeted approaches. Indeed, we have a lot of data that have been generated over the last decade or plus to show that the long-term benefits of significant reductions in LDL translate into very meaningful and very rapid onset reductions in risk of cardiovascular disease, which we have to remember is a substantial burden. Within that, on health care, and even, as I said earlier, within that population, there are subpopulations which are truly refractory and in a smaller size that enables us to, we believe, move rapidly through the regulatory space and actually create a meaningful business on which we can build into larger prevalent populations.
I think the other piece I want to just return to is that one of the things we've seen with editing in the clinical data to date, which I think is sometimes buried or lost because everybody focuses on the mean response. If you actually look at the variability of the clinical response in edited patients, it's much narrower than you see for other therapeutic modalities. Why does that matter? That matters because when you think about it, it means that the responder rate is going to be higher. I think that's a really important distinction that sometimes is lost because people are so focused on that single number in the middle, the mean.
A mean plus or - 1 is a very different value proposition for a mean plus or + 10 because that means that when you're talking about, and this is important for lifelong therapies, if you're thinking about how health systems and payers are going to look at that, they need to see a high responder rate or a low number needed to treat rate. That's a really important piece and something that I think is being missed. I shouldn't say that. It's important that we emphasize and highlight so that people actually see that.
Yeah, I think commercial viability and clinical significance are very important. We have to think about it earlier. Although for our first program, it's just in IND stage and hasn't started initiating a global phase one/two trial, we will interview with our KOL, the physicians, to understand the true medical need and the clinical significance it potentially could provide. Even thinking about the pricing strategy earlier because the current, what is the current standard of care? What is the pricing? How can we save how many standard of care? What is the pricing strategy? What is the cost of our therapy? Yeah, those factors all will count. Yeah.
Yeah, absolutely.
I should have said that, sorry, my apologies. One thing I left out, and you said it, but I just want to really emphasize it, is that there is a reason why all of us sitting up here are searching for systemic use, have moved to nanoparticles. Obviously, if you move into enclosed spaces, as Tian and Devyn have too, you can actually get your cost of goods low. That's important because ultimately, it's not just about popular shakes. It's about margins. Actually getting the right margin, getting the cost of goods low enables you to get the margins right for something that is going to actually deliver value to health care systems, very importantly, change patients' lives, but actually also create a viable business.
I think that was one of the things that we struggled with at the beginning because we were using incredibly high cost delivery technologies like cell therapies with vanishingly low margins, which were basically making people incredibly anxious. I think moving to a simplified systemic delivery using LNPs with low cost of goods or focal delivery with low cost of goods, high margins is actually going to be something that's really going to actually transform the business case.
I completely echo that. I just want to add in the gene and cell therapy space, probably gene editing cargo delivered by a non-viral approach is the option with the highest chance of commercial viability, given the extremely low cost of goods, order of magnitude lower cost of goods. I think that's where the field is going. Personally, I don't think it's ethical to make blockbuster drugs costing millions of dollars for rare disease patients. Especially in our experience, many of these patients and their families are not doing well economically to start with. Without a mature payer system like the U.S. and EU, the vast majority of the global population have no chance to access the benefit of gene editing with the current price tag. Non-viral is, I believe, so far the only way to go for the global south.
Yeah. Yeah, there's absolutely cost and cost advantages both from a pharmacoeconomics standpoint and from an investment case standpoint. Allan, did you have something to say? You looked like you were about to say something.
Yeah, no. I mean, I would just say these are transformational therapies, which the world really hasn't seen these types of things before, right? I would say this is very differentiated from gene therapy, which would be the only kind of close caller. It's too different. To me, this is going to transform patient treatment over the coming years and decades. The commercial, it's going to be a, I don't worry kind of how these companies are going to do commercially because I just think we're just scratching the surface of what we can do. I think from an investor standpoint, at some point, you've got to see it before you believe it. Because it's so new, they just have to understand how that's going to work. The last thing I'll just say is it's all about the business model, right?
I think many of the companies started out and just kind of worked everywhere. I'll say the market maybe forced a lot of us to really focus on the right commercial opportunities for the right reasons. I would say companies today are more disciplined. I think everything that companies are going after, and if you look at pipelines today, they're typically now really focused on where can we be successful commercially.
Great. In the last minute or so, any closing thoughts for where you think the space is going and what we should look out for in the next few years? Again, keep that open.
I think you're going to see multiple approvals. I think you're going to see multiple launches. I think that you, what's the other thing I want to say? I think you're actually going to see what Allan just said, people are going to see what they need to see to believe. I think after the first wave of high technical success and some commercial challenges, I believe that the payer landscape is actually evolving. We'll have had a chance to sort of say, oh, hang on. Oh, this is coming. This is real. We'll adjust because historically, sometimes those systems have lagged behind the technology and the therapeutic launch. I actually think the next five years are going to be incredibly exciting in the space, not just technically, but actually just from a point of view of showing the true robust business viability of this approach to therapeutics.
Yeah. Great. I see we're getting the flashing times up sign. I think that brings us to the end of our session. Thank you all again for participating and for the fantastic discussion.
Thank you. It was really nice having you. Give it a moment.